Since corneal nerve is severed by corneal surgeries such as Laser photorefractive keratectomy (PRK), Laser-Assisted-In-Situ Keratomileusis (LASIK), keratoplasty and the like, the functional reduction of corneal sensitivity is said to occur for generally about 3 weeks to one year. For example, it has been reported that the corneal nerve is apparently severed after LASIK (Tuuli U. Linna et al., Experimental Eye Research 66: 755-763, 1998), and the corneal sensitivity decreases in a corneal region where, after LASIK, neurogram is not observed or the nerve bundle is too short to create connection (Tuuli U. Linna et al., Investigative Ophthalmology & Visual Sciences, 41: 393-397, 2000).
It has been demonstrated that the corneal hyposensitivity after PRK and LASIK causes lower lacrimal gland response and decreased lacrimal fluid (Ang, Robert T. et al., Current Opinion in Ophthalmology 12: 318-322, 2001). As a result of the hypofunction of corneal sensitivity, patients after a corneal surgery blink less number of times, problematically showing the symptoms of dry eye. In the patients with dry eye, lacrimal hypofunction gives rise to corneal hyposensitivity, which, upon combination with further lacrimal hypofunction, problematically aggravates the condition of corneal surface.
At present, however, recovery of corneal hyposensitivity after corneal surgery is left to spontaneous recovery, and in the treatment of dry eye, no active treatment is provided to recover corneal sensitivity. Moreover, while corneal hyposensitivity is caused by the diseases accompanying corneal neurodegeneration, such as neuroparalytic keratopathy, corneal ulcer, diabetic keratopathy and the like, no appropriate cure is available at present.
Rho-kinase is a serine/threonine kinase activated along with the activation of Rho, which is a low molecular weight G protein, and is known to control diversified physiological functions such as smooth muscle contraction, neurite retraction and the like, by phosphorylation of various substrates. A compound having an inhibitory activity of such Rho-kinase is expected to provide various pharmaceutical uses and there has been suggested use as a therapeutic drug for, for example, hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, arteriosclerosis, osteoporosis, retinopathy and the like, as well as an anti-cancer drug, an anti-inflammatory drug, an immunosuppressant and the like (e.g., WO98/06433). In addition, Rho-kinase inhibitors are known to be useful for the improvement of visual function disorder, since they have an axon extension action of retinal ganglion cells (WO02/083175). Due to this action, Rho-kinase inhibitors are considered to promote regeneration of optic nerve cells and be useful for the treatment of visual function disorders associated with various eye diseases caused by damage, defect, degeneration and the like of retina and optic nerve. However, this reference does not at all describe effects of Rho-kinase inhibitor on corneal diseases such as corneal hyposensitivity and the like.
The corneal sensitivity is controlled by trigeminal nerve (corneal nerve), which is a sensory nerve distributed in the cornea. As regards the relationship between Rho and the trigeminal nerve, it has been reported that, in a rat trigeminal nerve tissue culture (trigeminal tract in whole mount cultures) system, neurotrophin (e.g., nerve growth factor (NGF) etc.)—induced extension of nerve axon is inhibited by a Rho activator (lysophosphatidic acid), and facilitated by introduction of dominant negative Rho into a cell (Ozdinler, P. Hande et al., The Journal of Comparative Neurology, 438:377-387, 2001). However, there is a description that whether Rho is effective for trigeminal nerve axon extension in the absence of neurotrophin is unknown (Ozdinler, P. Hande et al., The Journal of Comparative Neurology, 438:377-387, 2001), and the effect of a Rho-kinase inhibitor on the trigeminal nerve has not been elucidated.
There are references teaching that compounds that promote neuron regeneration or neurite outgrowth are usable for the treatment of corneal nerve damage after surgery such as LASIK and the like, and as examples of such compounds, Neotrofin, which is a neurotrophic factor stimulator, and the like are shown (WO03/020281). However, WO03/020281 does not at all describe Rho-kinase or an inhibitor thereof, or any description suggestive thereof.